Fig. 1.

Pathogenesis of Clostridium difficile. When C. difficile spores are ingested, they are stimulated to germinate by bile salts (e.g. taurocholate) in the small intestine. C. difficile can productively colonize the colon of individuals whose normal intestinal flora has been disrupted (e.g. by antibiotic treatment). Colonization likely depends upon adherence of the bacterium to the epithelium, although little is known about the factors that mediate adherence. CDT-producing strains may increase their adherence to intestinal epithelial cells by inducing microtubule protrusions that trap C. difficile. Glucosylating toxin-producing strains stimulate inflammation of the colonic lining by inducing cytoskeletal changes that compromise the epithelial barrier and inflammatory cytokine production. Disruption of tight junctions allows the toxins to cross the epithelium, where they can further induce inflammatory cytokine production in lymphocytes and mast cells. This leads to escalation of the inflammatory response due to neutrophil and lymphocyte influx, which can lead to pseudomembrane formation. Whether glucosylating toxins enter the bloodstream remains unclear, although in a zebrafish model of infection, the toxins can become systemic [78]. During colonization of the host, C. difficile produces spores that are shed by the patient and facilitate transmission of C. difficile to susceptible hosts.